TY - JOUR
T1 - Hdac3 restrains cd8-lineage genes to maintain a bi-potential state in cd4+cd8+ thymocytes for cd4-lineage commitment
AU - Philips, Rachael Laura
AU - Lee, Jeong Heon
AU - Gaonkar, Krutika
AU - Chanana, Pritha
AU - Chung, Ji Young
AU - Arocha, Sinibaldo R.Romero
AU - Schwab, Aaron
AU - Ordog, Tamas
AU - Shapiro, Virginia Smith
N1 - Funding Information:
We thank Dr. Scott Hiebert for HDAC3 floxed mice. This work benefitted from data assembled by the Immunological Genome Consortium. We thank members of the Epigenomics Program and Medical Genome Facility within the Center for Individualized Medicine for their contributions to the generation of ChIP-seq and RNA-seq datasets. We also thank members of the VSS and Kay Medina (Mayo Clinic) laboratory for thoughtful discussions and critical reading of the manuscript. This work was supported by National Institutes of Health Grants R56 AI122746 and T32 AI007425, Center for Biomedical Discovery at Mayo Clinic, Mayo Graduate School funds to RLP, and Mayo Foundation funds to VSS. The authors do not have any conflicts of interest.
Publisher Copyright:
Copyright Philips et al.
PY - 2019
Y1 - 2019
N2 - CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
AB - CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
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U2 - 10.7554/eLife.43821
DO - 10.7554/eLife.43821
M3 - Article
C2 - 30657451
AN - SCOPUS:85060142676
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e43821
ER -